introduction on lung cancer essay

Introduction to Lung Cancer

Lung cancer is the second most common cancer , accounting for about one out of five malignancies in men and one out of nine in women. Unfortunately, over the past several years, while the incidence of lung cancer has gradually declined in men, it has been rising alarmingly in women. In 1940 only seven women in 100,000 developed the disease; today the rate is 42 in 100,000. And all the evidence points to smoking as the cause. As one specialist in the field reports, "How long it takes to get cancer depends on how many cigarettes you smoke a day." However, studies prove that quitting smoking does lower the risk .

There are two major types of lung cancer: small cell lung cancer (SCLC)—which is also called oat cell cancer, because the cells resemble oat grains—and non-small cell lung cancer (NSCLC). The aggressiveness of the disease and treatment options depend on the type of tumor diagnosed. Because many types of lung cancer grow quickly and spread rapidly and because the lungs are vital organs, early detection and prompt treatment—usually surgery to remove the tumor—is critical.

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Lung cancer: introduction, what is cancer.

Cancer may seem complex. But at its core, cancer is simple. Normal cells grow and die when your body needs them to. Cancer is what happens when certain cells grow even though your body doesn’t need them.

In many cases, these cancerous cells form a lump or mass called a tumor. Since cancerous cells don’t act like normal cells, tumors can prevent your body from working correctly. Given time, they can also spread, or metastasize, to other parts of the body.

Lung cancer is cancer that starts in the cells that make up the lungs. It isn’t cancer that spreads to the lungs from other parts of the body. This is key because treatment is based on the original site of the tumor. For example: If a tumor begins in the breast and spreads to the lungs, it would be treated as metastatic breast cancer—not lung cancer.

Understanding the lungs

The lungs are sponge-like organs in your chest. Their job is to bring oxygen into the body and to get rid of carbon dioxide. When you breathe air in, it goes into your lungs through your windpipe (trachea). The trachea divides into tubes called bronchi, which enter the lungs. These divide into smaller branches called bronchioles. At the end of the bronchioles are tiny air sacs called alveoli. The alveoli move oxygen from the air into your blood. They take carbon dioxide out of the blood. This leaves your body when you breathe out (exhale).

Your right lung is divided into 3 sections (lobes). Your left lung has 2 lobes.

Types of lung cancer

There are two main types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Understanding the differences between these types may lessen anxiety about your diagnosis and treatment.

Non-small cell lung cancer

NSCLC accounts for 85% to 90% of lung cancer cases. There are 3 main subtypes. Each subtype is named for the type of cell it develops in:

Adenocarcinoma. This is the most common type of lung cancer—particularly among the minority of non-smokers who get the disease. It tends to appear on the outer edges of the lungs and grows more slowly than the other subtypes. 

Squamous cell carcinoma (epidermoid carcinoma). This type of cancer develops more often in smokers or former smokers than lifetime nonsmokers. It tends to start in the center of the lungs near the bronchial tubes.

Large cell carcinoma.  The least common NSCLC, large cell carcinoma can begin anywhere in the lung. It tends to grow more quickly than the other subtypes, which can make it harder to treat.

Despite minor differences, they are often treated the same way.

Small cell lung cancer

Only about 1 in 10 to 3 in 20 people diagnosed with lung cancer have small-cell lung cancer (also called oat cell cancer). It's also almost exclusively found in smokers. It tends to grow more quickly than NSCLC. It often spreads to other parts of the body at an earlier stage.

How lung cancer spreads

Lung cancer acts differently in different people. But when it spreads, it tends to go to the same places. First: lymph nodes in the center of the chest. It may also spread to lymph nodes in the lower neck.

Lymph nodes are small clusters of immune system cells.

During later stages, lung cancer may spread to more distant parts of the body, such as the liver, brain, or bones.

Talk with your healthcare provider

If you have questions about lung cancer, talk with your healthcare provider. They can help you understand more about this cancer. 

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Lung cancer begins in the cells of the lungs.

Lung cancer is a kind of cancer that starts as a growth of cells in the lungs. The lungs are two spongy organs in the chest that control breathing.

Lung cancer is the leading cause of cancer deaths worldwide.

People who smoke have the greatest risk of lung cancer. The risk of lung cancer increases with the length of time and number of cigarettes smoked. Quitting smoking, even after smoking for many years, significantly lowers the chances of developing lung cancer. Lung cancer also can happen in people who have never smoked.

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Lung cancer typically doesn't cause symptoms early on. Symptoms of lung cancer usually happen when the disease is advanced.

Signs and symptoms of lung cancer that happen in and around the lungs may include:

• A new cough that doesn't go away.
• Chest pain.
• Coughing up blood, even a small amount.
• Hoarseness.
• Shortness of breath.

Signs and symptoms that happen when lung cancer spreads to other parts of the body may include:

• Losing weight without trying.
• Loss of appetite.
• Swelling in the face or neck.

When to see a doctor

Make an appointment with your doctor or other healthcare professional if you have any symptoms that worry you.

If you smoke and haven't been able to quit, make an appointment. Your healthcare professional can recommend strategies for quitting smoking. These may include counseling, medicines and nicotine replacement products.

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Lung cancer happens when cells in the lungs develop changes in their DNA. A cell's DNA holds the instructions that tell a cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions tell the cells to die at a set time. In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to make many more cells quickly. Cancer cells can keep living when healthy cells would die. This causes too many cells.

The cancer cells might form a mass called a tumor. The tumor can grow to invade and destroy healthy body tissue. In time, cancer cells can break away and spread to other parts of the body. When cancer spreads, it's called metastatic cancer.

Smoking causes most lung cancers. It can cause lung cancer in both people who smoke and in people exposed to secondhand smoke. But lung cancer also happens in people who never smoked or been exposed to secondhand smoke. In these people, there may be no clear cause of lung cancer.

How smoking causes lung cancer

Researchers believe smoking causes lung cancer by damaging the cells that line the lungs. Cigarette smoke is full of cancer-causing substances, called carcinogens. When you inhale cigarette smoke, the carcinogens cause changes in the lung tissue almost immediately.

At first your body may be able to repair this damage. But with each repeated exposure, healthy cells that line your lungs become more damaged. Over time, the damage causes cells to change and eventually cancer may develop.

Types of lung cancer

Lung cancer is divided into two major types based on the appearance of the cells under a microscope. Your healthcare professional makes treatment decisions based on which major type of lung cancer you have.

The two general types of lung cancer include:

• Small cell lung cancer. Small cell lung cancer usually only happens in people who have smoked heavily for years. Small cell lung cancer is less common than non-small cell lung cancer.
• Non-small cell lung cancer. Non-small cell lung cancer is a category that includes several types of lung cancers. Non-small cell lung cancers include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.

Risk factors

A number of factors may increase the risk of lung cancer. Some risk factors can be controlled, for instance, by quitting smoking. Other factors can't be controlled, such as your family history.

Risk factors for lung cancer include:

Your risk of lung cancer increases with the number of cigarettes you smoke each day. Your risk also increases with the number of years you have smoked. Quitting at any age can significantly lower your risk of developing lung cancer.

Exposure to secondhand smoke

Even if you don't smoke, your risk of lung cancer increases if you're around people who are smoking. Breathing the smoke in the air from other people who are smoking is called secondhand smoke.

Previous radiation therapy

If you've had radiation therapy to the chest for another type of cancer, you may have an increased risk of developing lung cancer.

Exposure to radon gas

Radon is produced by the natural breakdown of uranium in soil, rock and water. Radon eventually becomes part of the air you breathe. Unsafe levels of radon can build up in any building, including homes.

Exposure to cancer-causing substances

Workplace exposure to cancer-causing substances, called carcinogens, can increase your risk of developing lung cancer. The risk may be higher if you smoke. Carcinogens linked to lung cancer risk include asbestos, arsenic, chromium and nickel.

Family history of lung cancer

People with a parent, sibling or child with lung cancer have an increased risk of the disease.

Complications

Lung cancer can cause complications, such as:

Shortness of breath

People with lung cancer can experience shortness of breath if cancer grows to block the major airways. Lung cancer also can cause fluid to collect around the lungs and heart. The fluid makes it harder for the affected lung to expand fully when you inhale.

Coughing up blood

Lung cancer can cause bleeding in the airway. This can cause you to cough up blood. Sometimes bleeding can become severe. Treatments are available to control bleeding.

Advanced lung cancer that spreads can cause pain. It may spread to the lining of a lung or to another area of the body, such as a bone. Tell your healthcare professional if you experience pain. Many treatments are available to control pain.

Fluid in the chest

Lung cancer can cause fluid to accumulate in the chest, called pleural effusion. The fluid collects in the space that surrounds the affected lung in the chest cavity, called the pleural space.

Pleural effusion can cause shortness of breath. Treatments are available to drain the fluid from your chest. Treatments can reduce the risk that pleural effusion will happen again.

Cancer that spreads to other parts of the body

Lung cancer often spreads to other parts of the body. Lung cancer may spread to the brain and the bones.

Cancer that spreads can cause pain, nausea, headaches or other symptoms depending on what organ is affected. Once lung cancer has spread beyond the lungs, it's generally not curable. Treatments are available to decrease symptoms and to help you live longer.

There's no sure way to prevent lung cancer, but you can reduce your risk if you:

Don't smoke

If you've never smoked, don't start. Talk to your children about not smoking so that they can understand how to avoid this major risk factor for lung cancer. Begin conversations about the dangers of smoking with your children early so that they know how to react to peer pressure.

Stop smoking

Stop smoking now. Quitting reduces your risk of lung cancer, even if you've smoked for years. Talk to your healthcare team about strategies and aids that can help you quit. Options include nicotine replacement products, medicines and support groups.

Avoid secondhand smoke

If you live or work with a person who smokes, urge them to quit. At the very least, ask them to smoke outside. Avoid areas where people smoke, such as bars. Seek out smoke-free options.

Test your home for radon

Have the radon levels in your home checked, especially if you live in an area where radon is known to be a problem. High radon levels can be fixed to make your home safer. Radon test kits are often sold at hardware stores and can be purchased online. For more information on radon testing, contact your local department of public health.

Avoid carcinogens at work

Take precautions to protect yourself from exposure to toxic chemicals at work. Follow your employer's precautions. For instance, if you're given a face mask for protection, always wear it. Ask your healthcare professional what more you can do to protect yourself at work. Your risk of lung damage from workplace carcinogens increases if you smoke.

Eat a diet full of fruits and vegetables

Choose a healthy diet with a variety of fruits and vegetables. Food sources of vitamins and nutrients are best. Avoid taking large doses of vitamins in pill form, as they may be harmful. For instance, researchers hoping to reduce the risk of lung cancer in people who smoked heavily gave them beta carotene supplements. Results showed the supplements increased the risk of cancer in people who smoke.

Exercise most days of the week

If you don't exercise regularly, start out slowly. Try to exercise most days of the week.

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• Small cell lung cancer. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462. Accessed Dec. 4, 2023.
• Niederhuber JE, et al., eds. Cancer of the lung: Non-small cell lung cancer and small cell lung cancer. In: Abeloff's Clinical Oncology. 6th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 4, 2023.
• Non-small cell lung cancer treatment (PDQ) – Patient version. National Cancer Institute. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq. Accessed Dec. 4, 2023.
• Small cell lung cancer treatment (PDQ) – Patient version. National Cancer Institute. https://www.cancer.gov/types/lung/patient/small-cell-lung-treatment-pdq. Accessed Dec. 4, 2023.
• Lung cancer – non-small cell. Cancer.Net. https://www.cancer.net/cancer-types/lung-cancer/view-all. Accessed Dec. 4, 2023.
• Lung cancer – small cell. Cancer.Net. https://www.cancer.net/cancer-types/33776/view-all. Accessed Dec. 4, 2023.
• Detterbeck FC, et al. Executive Summary: Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; doi:10.1378/chest.12-2377.
• Palliative care. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1454. Accessed Dec. 4, 2023.
• Lung cancer. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/lung-cancer. Accessed Dec. 4, 2023.
• Cairns LM. Managing breathlessness in patients with lung cancer. Nursing Standard. 2012; doi:10.7748/ns2012.11.27.13.44.c9450.
• Warner KJ. Allscripts EPSi. Mayo Clinic. Jan. 13, 2020.
• Brown AY. Allscripts EPSi. Mayo Clinic. July 30, 2019.
• Searching for cancer centers. American College of Surgeons. https://www.facs.org/search/cancer-programs. Accessed Dec. 4, 2023.
• Temel JS, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. New England Journal of Medicine. 2010; doi:10.1056/NEJMoa1000678.
• Dunning J, et al. Microlobectomy: A novel form of endoscopic lobectomy. Innovations. 2017; doi:10.1097/IMI.0000000000000394.
• Leventakos K, et al. Advances in the treatment of non-small cell lung cancer: Focus on nivolumab, pembrolizumab and atezolizumab. BioDrugs. 2016; doi:10.1007/s40259-016-0187-0.
• Dong H, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine. 1999;5:1365.
• Aberle DR, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine. 2011; doi:10.1056/NEJMoa1102873.
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• Volume 57, Issue 11
• Lung cancer • Introduction
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• Correspondence to: T Sethi, Respiratory Medicine Unit, Department of Medicine, Rayne Laboratory, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, UK; t.sethi{at}ed.ac.uk

A series of review articles on lung cancer beginning in this issue of Thorax aims to increase the awareness of up to date evidence based knowledge and to generate further interest and optimism in its diagnosis and management.

• lung cancer

https://doi.org/10.1136/thorax.57.11.992

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Lung cancer is the commonest fatal malignancy in the developed world causing over 40 000 deaths in the UK per annum. While the incidence of lung cancer in men is beginning to fall in the West, the incidence of lung cancer in women continues to rise and in a number of countries has overtaken breast cancer. In developing nations where smoking rates are high, the high mortality will continue to rise well into the century. In addition, the incidence of mesothelioma has been steadily increasing over the past 30 years and this is expected to continue for the next 20 years. Despite this epidemic, it is salutary to consider that in the Queen’s Jubilee Year there has been little change in the 5 year survival for lung cancer since the Queen’s father, George VI, died from lung cancer in 1952. In the UK fewer than 5% of patients are alive less than 5 years after diagnosis. This review series attempts to show the way forward to improve these poor survival figures.

Smoking remains the principal cause of lung cancer and preventing young people from smoking and improved smoking cessation strategies are therefore extremely important. These topics have been recently well reviewed and will not be reviewed further in this series. Only 10% of smokers go on to develop lung cancer, so genetic and dietary risk factors play an import role in the pathogenesis. The fact that cigarette smoking will not be easily or rapidly eradicated from society has increased interest in chemoprevention strategies.

One of the causes of the poor survival rates seen in the UK compared with Europe and North America may in part be due to patients presenting later with more advanced disease and consequently poorer performance status. Compared with the other common malignancies (breast, prostate and cervical cancer), lung cancer is more frequently diagnosed at an advanced metastatic stage. Lung cancer is an ideal disease for a population based screening programme because we can easily identify the at risk group. Older screening studies have failed to demonstrate any impact on survival and, though highly sensitive, CT scanning was not felt to be useful in screening for lung cancer because there were many false positives. However, optimising all aspect of the screening process and subsequent management, together with technological innovations (both radiological and cellular/molecular biology), offers the potential for detecting lung cancers at a much earlier stage than was previously possible, hopefully leading to more curative treatment and improved survival.

While the majority of patients with lung cancer present with advanced disease precluding curative treatment, advances are being made in palliative chemotherapy and radiotherapy. There is increasing evidence and understanding that both these treatment modalities can improve survival, palliate and enhance quality of life. In addition, newer chemotherapeutic agents and novel treatment regimens are emerging which may be less toxic and have greater efficacy. While standard treatment modalities are producing incremental improvements in quality of life, survival, and cure of patients with lung cancer, the advances in molecular technologies are providing insights into the pathobiology of lung cancer development which have the potential to provide novel rational therapeutic strategies for early diagnosis, risk assessment, prevention, and treatment of this devastating disease.

The peak incidence of lung cancer is between 75 and 80 years of age in the UK. Over half of the 500 000 patients diagnosed annually worldwide with lung cancer are over 70 years old. This will present a major challenge to health services. There are a number of myths and prejudices about the management of lung cancer in the elderly. Older patients are less likely to be investigated and less likely to receive curative or palliative treatment, despite little evidence that age is a significant independent adverse prognostic factor in any treatment modality. Age per se should not preclude histological diagnosis, staging, and treatment.

Whether age is a risk factor for lung cancer surgery remains controversial. Evidence to date would suggest that the elderly can do as well as younger age groups. With modern surgical practice, elderly patients may derive further benefit. However, the extent of surgical resection required in the treatment of patients with operable lung cancer is controversial. There is increasing evidence that limited surgical resection would increase the number of patients suitable for surgery and reduce perioperative morbidity and mortality. Limited surgical resection, combined with screening for earlier diagnosis of smaller tumours (less than 3 cm), may constitute an effective form of treatment for elderly patients or patients with significant medical co-morbidities.

The UK has one of the lowest rates of investigation, lowest resection rates, and lowest use of curative and palliative treatments in the developed world and, as a consequence, it has the lowest survival and cure rates. It is important to remember at a time when the Government and the Health Service are increasingly responsive to patients’ wishes that, despite the imprecise state of our knowledge about early lung cancer detection and lung cancer treatment, many patients at high risk may still want to undergo lung cancer testing, and patients with lung cancer would want to have the best available treatment despite relatively modest improvements in medium survival and cure. Ideally, patients with lung cancer should be investigated and treated in a centre of excellence as epitomised by the “One Stop” Lung Cancer Service at Papworth Hospital. These centres must be properly resourced and staffed by an enthusiastic multidisciplinary team committed to the integrated care of patients with lung cancer. The national shortage of lung pathologists, specialist radiologists, specialist nurses, and thoracic surgeons must be addressed to ensure the development of this type of service throughout the country.

Lung cancer is a common problem and a major cause of morbidity and death. The generally poor prognosis of patients has generated a degree of pessimism and nihilism among physicians. Lung cancer is more common than breast cancer and cervical cancer, but if one compares the resources devoted to patient care and research, or the number of specialist clinics and healthcare professionals with a declared interest, lung cancer always seems to come a poor second.

This review series aims to improve the overall understanding of lung cancer. Areas of debate and controversy have been highlighted. Many of the questions raised in this review series could be resolved by well conducted multicentre clinical trials. Unfortunately, at the present time only a minority of patients are included in studies. Wider participation in both clinical and basic research will lead to higher standards of care essential for future improvement in the survival and cure of patients with lung cancer. It is hoped that increased awareness of up to date evidence-based knowledge and the important questions that need to be addressed will generate further interest and optimism for the diagnosis and management of patients with lung cancer.

• West R , McNeill A, Raw M. Smoking cessation guidelines for health professionals: an update. Thorax 2000 ; 55 : 987 –99. OpenUrl Abstract / FREE Full Text
• Sutherland G . Current approaches to the management of smoking cessation. Drugs 2002 ; 62 (Suppl 2): 53 –61 (and other related articles). OpenUrl

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• Richard D Neal , professor of primary care oncology 1 ,
• Fei Sun , clinical research fellow, honorary specialty registrar in clinical oncology 2 ,
• Jon D Emery , Herman professor of primary care cancer research 3 ,
• Matthew E Callister , consultant respiratory physician 2
• 1 Academic Unit of Primary Care, Leeds Institute of Health Sciences, University of Leeds, Leeds LS2 9NL, UK
• 2 Leeds Teaching Hospitals Trust, St James’s Hospital, Leeds LS9 7TF, UK
• 3 Centre for Cancer Research and Department of General Practice, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victorian Comprehensive Cancer Centre, Victoria 3000, Australia
• Correspondence to: R D Neal R.D.Neal{at}leeds.ac.uk

What you need to know

Most lung cancers present with non-specific symptoms; haemoptysis is a feature in only 20%

Consider a chest x ray for patients who have persistent symptoms or thrombocytosis, and repeat chest x ray or computed tomography (CT) if symptoms persist

Positron emission tomography-computed tomography (PET-CT) is used to identify distant metastases in those eligible for radical treatment after contrast-enhanced CT. If there is potential mediastinal node involvement, endobronchial ultrasound guided transbronchial needle aspiration is the optimal initial strategy for nodal sampling

Surgery remains the standard of care in early stage non-small cell lung cancer (NSCLC). Radical radiotherapy or stereotactic ablative radiotherapy (SABR) are alternatives. Options for locally advanced NSCLC include surgery with postoperative chemotherapy or chemoradiotherapy

Systemic therapy for metastatic NSCLC is now targeted primarily on tumour genetic mutations and biomarkers. Tyrosine-kinase inhibitor (TKIs) and immunotherapy are first line treatments for some patients with metastatic NSCLC. Combination chemotherapy is available for patients not eligible for TKIs or immunotherapy

Lung cancer is one of the commonest cancers worldwide. 1 Outcomes are among the poorest of all tumour types, with five year survival of 10-20%. 2 Survival is hugely influenced by stage at diagnosis, with five year survival varying from 92% to 0% for the earliest and latest stages respectively. 3 In this update we discuss contemporary therapeutic options, and approaches to increasing symptom awareness and early diagnosis. Low-dose computed tomography (CT) screening is beyond the scope of this review.

Sources and selection criteria

In addition to searching Clinical Evidence and the Cochrane Collaboration, we based this article on databases of references. We also examined the citation lists of included articles.

Who gets it?

Worldwide, about three quarters of lung cancers are attributable to smoking; others are caused by occupational workplace exposure, radon exposure, and air pollution. 4 It is more common in men, and incidence increases with age ( fig 1 ). Recent evidence suggests a changing pattern of lung cancer with higher incidence in younger and non-smoking women, especially in Asia and countries with Asian migrant populations. 5 As smoking rates decline in some countries, there will be a fall in incidence, but this will be in decades to come. The most effective intervention for reducing lung cancer mortality remains smoking cessation; hence better interventions to reduce smoking are imperative. Radon remediation in certain areas may also be of benefit.

Incidence of lung cancer per 100 000 population by age and sex in UK 2013-15 (adapted from Cancer Research UK. Lung cancer incidence by age. 2017. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/incidence#heading-One )

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How can we improve symptom awareness in people at risk?

Several studies have explored symptom appraisal and help-seeking in people with recently diagnosed lung cancer. Factors associated with later presentation include limited awareness of cancer symptoms and fear of cancer, 6 concerns about wasting their own and general practitioners’ time, 7 and stoicism and stigma around smoking. 8

Mass-media campaigns for symptom awareness are one approach to reducing the time that patients take to seek help about symptoms. Evidence from the “Be Clear on Cancer” campaigns in England reported potentially useful short term effects, including increased presentations to general practice and a higher proportion of earlier stage cancers 9 ; similarly, a significant shift to earlier cancer stage at presentation was seen after a local symptom awareness campaign. 10 A trial of a cancer symptom awareness campaign, including lung cancer, in rural Western Australia did not reduce time to diagnosis, although this may have been due to the absence of television advertising. 11 There is recent evidence suggesting that early awareness campaigns have the potential to be cost-effective. 12 Social media may also have a role in raising awareness.

An alternative to mass-media campaigns is to focus symptom awareness interventions on individuals at increased risk. A behavioural intervention aimed at reducing barriers to help-seeking in current or former heavy smokers over 55 years old reported a significant positive impact on consultation rates in Scotland, 13 and an increase in respiratory consultations in Australia. 14

How should primary care clinicians respond to patients with symptoms?

For England and Wales, the National Institute for Health and Care Excellence (NICE) provides guidance on the criteria that warrant urgent action. 15 For example, referral is recommended for unexplained haemoptysis in people aged over 40 years, and urgent chest x ray is recommended in smokers with appetite loss or with thrombocytosis. However, the presentation of symptoms is often complex, as many people will have comorbidities, 16 and there is often no clear symptom signature. 17

Only half of patients will have an isolated first symptom, and, although haemoptysis is the most predictive symptom, it occurs in only 20% patients. 18 Many patients present with non-respiratory symptoms. Hence prompt recognition of patients who do not fulfil NICE criteria depends on clinicians having a low threshold for requesting a chest x ray, and a low threshold for repeating or requesting further lung imaging if patients have a normal chest x ray and ongoing symptoms. Some national guidelines suggest computed tomography in the case of persistent symptoms despite a normal chest x ray. 19 Several risk prediction tools have been developed for use in primary care, but there is insufficient evidence to recommend their use. 20

The prospect of biomarkers to identify people with early disease is of considerable interest. This includes novel technologies to detect volatile organic compounds in the breath and blood biomarkers.

How can we redesign health systems to improve diagnosis and treatment?

The NHS in England has recently implemented a timed lung cancer diagnostic pathway aiming to streamline investigations for suspected lung cancer, allowing earlier treatment alongside a more rapid “all clear” for patients found not to have cancer. 21

The variations seen between treating centres are thought to contribute to poorer UK outcomes. An estimated 500 deaths could be prevented annually if the proportions of patients treated with surgery and radical radiotherapy matched those in centres in the highest quintile of treatment rates. 22 Similarly, there is known variation between general practitioners in their propensity to investigate patients equally. 23

What imaging, diagnostic work-up, and treatment planning should be undertaken?

The starting point is contrast-enhanced computed tomography (CT) of the thorax including neck and upper abdomen ( fig 2 ). If initial CT demonstrates distant metastases or involvement of the supraclavicular or cervical lymph nodes, sampling allows staging and pathological subtyping (immunohistochemical and molecular analysis) in one procedure. If the disease seems suitable for radical treatment (either surgical or oncological), positron emission tomography-computed tomography (PET-CT) is indicated due to its high sensitivity for distant metastases. PET-CT has lower specificity for mediastinal disease, so systematic nodal sampling is preferred when imaging has indicated possible nodal spread. This is usually performed by sampling under endoscopic ultrasound guidance (usually endobronchial ultrasound guided transbronchial needle aspiration) which is more sensitive and cost effective than surgical staging alone. 24

Computed tomography (CT) scan of the chest of a male patient with adenocarcinoma in the lower left lung (at right)

The requirements for pathological and genetic analysis of tumour biopsies have become more complex alongside the substantial increase in treatment options for advanced disease. The historical distinction between small cell and non-small cell lung carcinoma has evolved into more precise immunohistochemical subtyping between squamous and non-squamous non-small cell lung carcinoma, alongside assays that predict response to immunotherapy and genotyping to assess suitability for targeted therapies.

What are the latest management options?

Early stage disease.

Surgical lobectomy remains the preferred treatment for medically fit patients with operable early stage lung cancer, with radical radiotherapy a lower morbidity alternative for patients with limited physiological reserve. Recent developments include the roles of minimally invasive surgery and newer radiotherapy techniques.

Over recent years, practice has shifted from open lobectomy towards video-assisted thoracoscopic surgery. These two approaches showed similar outcomes in a large propensity matched analysis from the US. 25 To date there has been no randomised comparison, but a UK trial has recently completed recruitment and will report shortly. 26

Radical oncological treatment of early stage lung cancer has been revolutionised by the development of stereotactic ablative radiotherapy (SABR) for peripheral tumours. This delivers a higher dose than conventional radical radiotherapy and has better overall survival. 27 Several studies attempting to randomise between surgery and SABR have failed to recruit, although one study is ongoing in North America ( https://clinicaltrials.gov/ct2/show/NCT02984761 ).

Locally advanced disease

Treatment options for patients with locally advanced lung cancer (involving hilar or mediastinal lymph nodes) now recommended by NICE 28 include surgery with adjuvant (postoperative) chemotherapy or chemotherapy and radiotherapy given in combination. The updated NICE guidance also recommends consideration of chemoradiotherapy followed by surgery for some patients, although this is rare in practice. 28 The recommendation is based on a new meta-analysis showing improved progression-free survival with this approach. 29 There is evidence that immunotherapy after chemoradiotherapy is beneficial. 30 Management of localised small cell lung carcinoma is with chemoradiotherapy 31 ; prophylactic cranial irradiation reduces brain metastases and improves survival.

Metastatic disease

There have been considerable recent changes in the management of metastatic non-small cell lung carcinoma. For patients whose tumours harbour epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations, tyrosine kinase inhibitors are the treatment of choice, with second line agents (third generation tyrosine kinase inhibitors or cytotoxic chemotherapy) reserved for those who progress or develop resistance. Increasingly, other molecular targets are being exploited.

The management of patients without such mutations has been transformed by the advent of immune checkpoint inhibitors (immunotherapy). Precise indications for immunotherapy (monotherapy versus combination treatment with chemotherapy, and first line versus second line treatment) depend on the extent to which the tumour expresses programmed death-ligand 1 (PD-L1), and the patient’s performance status (only licensed for use in relatively fit patients), with practice evolving at a rapid rate. For those patients ineligible for or not responding to immunotherapy, palliative chemotherapy remains the standard of care.

Metastatic small cell lung carcinoma is primarily managed with chemotherapy, and consolidation chest radiotherapy is beneficial for patients who respond to chemotherapy. 32

A small proportion of people with symptoms relating to airway occlusion by tumour may benefit from local treatment with stenting, argon plasma coagulation, or photodynamic therapy.

What interventions should be offered for people living with and beyond lung cancer?

Many patients with lung cancer and their families will need psychological support to help cope with the consequences of their diagnosis and treatment. Many patients continue to smoke after diagnosis, placing them at higher risk of treatment toxicity, cancer recurrence, second primaries, and poorer survival. 33 Quitting smoking after a diagnosis can improve prognosis regardless of cancer stage. 34 All patients who continue to smoke must be offered interventions to help them quit. Discussions should be conducted in a manner that minimises stigma and blaming.

The only randomised study of follow-up imaging found no survival benefit from regular computed tomography after surgical resection. 35 In patients with metastatic disease, palliative radiotherapy is effective in the management of symptoms such as pain and haemoptysis. Early input from palliative care should be considered for patients with advanced disease, including those receiving active treatment, although access may vary internationally. Early palliative care improves outcomes, including survival. 36

Additional educational resources

National Institute for Health and Care Excellence. Clinical Knowledge Summary: Symptoms suggestive of lung and pleural cancers. https://cks.nice.org.uk/lung-and-pleural-cancers-recognition-and-referral#!diagnosisSub

National Institute for Health and Care Excellence. Suspected cancer: recognition and referral (NICE guideline NG12). Section 1.1 Lung and pleural cancers. 2017. https://www.nice.org.uk/guidance/ng12/chapter/1-Recommendations-organised-by-site-of-cancer#lung-and-pleural-cancers

Patient.info. Professional articles: Lung cancer. 2017. https://patient.info/doctor/lung-cancer-pro

Information resources for patients

Patient.info. Lung cancer. 2017. https://patient.info/health/lung-cancer-leaflet

Cancer Research UK. Lung cancer. 2017. https://www.cancerresearchuk.org/about-cancer/lung-cancer

British Lung Foundation. Lung cancer. https://cdn.shopify.com/s/files/1/0221/4446/files/FL16_Lung_cancer_v3_2017_PDFdownload.pdf?3883777416736138941&_ga=2.86724443.296111450.1537438735-81433678.1534270194

Roy Castle Lung Cancer Foundation. Lung cancer information. https://www.roycastle.org/how-we-help/lung-cancer-information

Macmillan Cancer Support. Information and support: Lung cancer. https://www.macmillan.org.uk/information-and-support/lung-cancer

Education into practice

Do you consider a chest x ray when a current or former smoker attends with non-specific symptoms?

Consider your last patient with lung cancer. Were there opportunities for earlier investigation and diagnosis?

Do you discuss early palliative care with all eligible patients?

Do you offer smoking cessation interventions to patients who continue to smoke after diagnosis?

How patients were involved in the creation of this article

Comments by a patient peer reviewer have been incorporated to help capture the patient perspective.

Contributors: RDN led the drafting of the introduction, “Who gets it,” and “How should primary care clinicians respond to patients with possible symptoms.” JDE led the drafting of “How can we improve symptom awareness in people at risk?” MCC led the drafting of “What imaging, diagnostic work-up, and treatment planning should be undertaken.” FS led the drafting of “What are the latest management options?” All authors contributed to improving these sections, and all authors contributed equally to the remaining sections. All authors have seen and approved the final version of the manuscript. We also thank Kevin Franks and Stephen Bradley for suggesting additional literature for inclusion in this review. RDN will act as guarantor.

Funding: RDN is an associate director and JDE is a member of senior faculty of the multi-institutional CanTest Collaborative, which is funded by Cancer Research UK (C8640/A23385). JDE is supported by an NHMRC Practitioner Fellowship.

Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Provenance and peer review: Commissioned, based on an idea from the author; externally peer reviewed.

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Lung cancer

Affiliations.

• 1 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia.
• 2 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
• 3 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Electronic address: [email protected].
• PMID: 34273294
• DOI: 10.1016/S0140-6736(21)00312-3

Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide with an estimated 2 million new cases and 1·76 million deaths per year. Substantial improvements in our understanding of disease biology, application of predictive biomarkers, and refinements in treatment have led to remarkable progress in the past two decades and transformed outcomes for many patients. This seminar provides an overview of advances in the screening, diagnosis, and treatment of non-small-cell lung cancer and small-cell lung cancer, with a particular focus on targeted therapies and immune checkpoint inhibitors.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Publication types

• Research Support, Non-U.S. Gov't
• Carcinoma, Non-Small-Cell Lung / diagnosis*
• Carcinoma, Non-Small-Cell Lung / therapy*
• Lung Neoplasms / diagnosis*
• Lung Neoplasms / therapy*
• Small Cell Lung Carcinoma / diagnosis*
• Small Cell Lung Carcinoma / therapy*

Lung Cancer Research Results and Study Updates

See Advances in Lung Cancer Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

FDA has approved alectinib (Alecensa) as adjuvant therapy for people with lung cancer who have ALK-positive tumors. In a clinical trial, alectinib helped people live longer after surgery without their cancer returning than chemotherapy.

The results of the clinical trial that led to FDA’s 2023 approval of repotrectinib (Augtyro) for lung cancers with ROS1 fusions have been published. The drug shrank tumors in 80% of people receiving the drug as an initial treatment.

A collection of material about the ALCHEMIST lung cancer trials that will examine tumor tissue from patients with certain types of early-stage, completely resected non-small cell lung cancer for gene mutations in the EGFR and ALK genes, and assign patients with these gene mutations to treatment trials testing post-surgical use of drugs targeted against these mutations.

Tarlatamab, a new type of targeted immunotherapy, shrank small cell lung cancer (SCLC) tumors in more than 30% of participants in an early-stage clinical trial. Participants had SCLC that had progressed after previous treatments with other drugs.

For people with lung cancer and medullary thyroid cancer whose tumors have changes in the RET gene, selpercatinib improved progression-free survival compared with other common treatments, according to new clinical trial results.

In the ADAURA clinical trial, people with early-stage lung cancer treated with osimertinib (Tagrisso) after surgery lived longer than people treated with a placebo after surgery. Despite some criticisms about its design, the trial is expected to change patient care.

For certain people with early-stage non-small cell lung cancer, sublobar surgery to remove only a piece of the affected lung lobe is as effective as surgery to remove the whole lobe, new research shows.

Pragmatica-Lung is a clinical trial for people with non-small cell lung cancer that has spread beyond the lungs (stage 4 cancer). The trial will help confirm if the combination of pembrolizumab and ramucirumab helps people with advanced lung cancer live longer.

On August 11, the Food and Drug Administration (FDA) gave accelerated approval to trastuzumab deruxtecan (Enhertu) for adults with non-small cell lung cancer (NSCLC) that has a specific mutation in the HER2 gene. Around 3% of people with NSCLC have this kind of HER2 mutation.

Giving people with early-stage lung cancer the immunotherapy drug nivolumab (Opdivo) and chemotherapy before surgery can substantially delay the progression or return of their cancer, a large clinical trial found.

Atezolizumab (Tecentriq) is now the first immunotherapy approved by FDA for use as an additional, or adjuvant, treatment for some patients with non-small cell lung cancer. The approval was based on results of a clinical trial called IMpower010.

Quitting smoking after a diagnosis of early-stage lung cancer may help people live longer, a new study finds. The study, which included more than 500 patients, also found that quitting smoking delayed the cancer from returning or getting worse.

NCI scientists and their international collaborators have found that the majority of lung cancers in never smokers arise when mutations caused by natural processes in the body accumulate. They also identified three subtypes of lung cancer these individuals.

FDA has approved the first KRAS-blocking drug, sotorasib (Lumakras). The approval, which covers the use of sotorasib to treat some patients with advanced lung cancer, sets the stage for other KRAS inhibitors already in development, researchers said.

Combining the chemotherapy drug topotecan and the investigational drug berzosertib shrank tumors in some patients with small cell lung cancer, results from an NCI-supported phase 1 clinical trial show. Two phase 2 trials of the combination are planned.

Mortality rates from the most common lung cancer, non-small cell lung cancer (NSCLC), have fallen sharply in the United States in recent years, due primarily to recent advances in treatment, an NCI study shows.

In a study of more than 50,000 veterans with lung cancer, those with mental illness who received mental health treatment—including for substance use—lived substantially longer than those who didn’t participate in such programs.

FDA has granted accelerated approval for selpercatinib (Retevmo) to treat certain patients with thyroid cancer or non-small cell lung cancer whose tumors have RET gene alterations. The drug, which works by blocking the activity of RET proteins, was approved based on the results of the LIBRETTO-001 trial.

Osimertinib (Tagrisso) improves survival in people with non-small cell lung cancer with EGFR mutations, updated clinical trial results show. People treated with osimertinib lived longer than those treated with earlier-generation EGFR-targeted drugs.

A large clinical trial showed that adding the immunotherapy drug durvalumab (Imfinzi) to standard chemotherapy can prolong survival in some people with previously untreated advanced small cell lung cancer.

The investigational drug selpercatinib may benefit patients with lung cancer whose tumors have alterations in the RET gene, including fusions with other genes, according to results from a small clinical trial.

FDA has approved entrectinib (Rozlytrek) for the treatment of children and adults with tumors bearing an NTRK gene fusion. The approval also covers adults with non-small cell lung cancer harboring a ROS1 gene fusion.

Clinical recommendations on who should be screened for lung cancer may need to be reviewed when it comes to African Americans who smoke, findings from a new study suggest.

Use of a multipronged approach within hospitals, including community centers, not only eliminated treatment disparities among black and white patients with early-stage lung cancer, it also improved treatment rates for all patients, results from a new study show.

In everyday medical care, there may be more complications from invasive diagnostic procedures performed after lung cancer screening than has been reported in large studies.

The Lung Cancer Master Protocol, or Lung-MAP, is a precision medicine research study for people with advanced non-small cell lung cancer that has continued to grow after treatment. Patients are assigned to different study drug combinations based on the results of genomic profiling of their tumors.

On December 6, 2018, the Food and Drug Administration (FDA) approved atezolizumab (Tecentriq) in combination with a standard three-drug regimen as an initial treatment for advanced lung cancer that does not have EGFR or ALK mutations.

A new study has identified a potential biomarker of early-stage non–small cell lung cancer (NSCLC). The biomarker, the study’s leaders said, could help diagnose precancerous lung growths and early-stage lung cancers noninvasively and distinguish them from noncancerous growths.

Results from two large clinical trials should cement the value of the drugs brigatinib (Alunbrig) and durvalumab (Imfinzi) in treating non-small cell lung cancer (NSCLC). The trial results, several experts said, confirm that the drugs can improve the outcomes of patients with advanced NSCLC.

Cancer researchers have trained a computer program to scan images of tissue samples to differentiate normal lung tissue from the two most common forms of lung cancer. The program also learned to detect cancer-related genetic mutations in the samples.

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Recent advances in lung cancer research: unravelling the future of treatment

• Review Article
• Published: 06 April 2024

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• Luca Bertolaccini   ORCID: orcid.org/0000-0002-1153-3334 1 ,
• Monica Casiraghi 1 , 2 ,
• Clarissa Uslenghi 1 ,
• Sebastiano Maiorca 1 &
• Lorenzo Spaggiari 1 , 2  

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Lung cancer, a multifaceted disease, demands tailored therapeutic approaches due to its diverse subtypes and stages. This comprehensive review explores the intricate landscape of lung cancer research, delving into recent breakthroughs and their implications for diagnosis, therapy, and prevention. Genomic profiling and biomarker identification have ushered in the era of personalised medicine, enabling targeted therapies that minimise harm to healthy tissues while effectively combating cancer cells. The relationship between pulmonary tuberculosis and lung cancer is examined, shedding light on potential mechanisms linking these two conditions. Early detection methods, notably low-dose computed tomography scans, have significantly improved patient outcomes, emphasising the importance of timely interventions. There has been a growing interest in segmentectomy as a surgical intervention for early-stage lung cancer in recent years. Immunotherapy has emerged as a transformative approach, harnessing the body's immune system to recognise and eliminate cancer cells. Combining immunotherapy with traditional treatments, such as chemotherapy and targeted therapies, has shown enhanced efficacy, addressing the disease's heterogeneity and overcoming drug resistance. Precision medicine, guided by genomic profiling, has enabled the development of targeted therapies like tyrosine kinase inhibitors, offering personalised treatments tailored to individual patients. Challenges such as drug resistance and limited accessibility to advanced therapies persist, emphasising the need for collaborative efforts and innovative technologies like artificial intelligence. Despite challenges, ongoing interdisciplinary collaborations and technological advancements offer hope for a future where lung cancer is treatable and preventable, reducing the burden on patients and healthcare systems worldwide.

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Acknowledgements

This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds.

Ministero della Salute, 5 × 1000, Ricerca Corrente.

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Bertolaccini, L., Casiraghi, M., Uslenghi, C. et al. Recent advances in lung cancer research: unravelling the future of treatment. Updates Surg (2024). https://doi.org/10.1007/s13304-024-01841-3

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Received : 06 March 2024

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Published : 06 April 2024

DOI : https://doi.org/10.1007/s13304-024-01841-3

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How to cite a letter, how to cite yourself, cause of lung cancer essay sample, example.

Among terminal diseases humanity has not yet learned to treat, cancer is probably one of the most feared illnesses. Unlike AIDS or other diseases widely spread in countries with low standards of living, cancer’s geography is much wider, including both rich and poor countries equally. Among the variety of different types of cancer, one of the most common is lung cancer; the environment in which people live in the 21st century greatly contributes to the development of this type of cancer.

The first and the most popular cause of lung cancer is smoking cigarettes. By numerous estimates, smoking cigarettes causes approximately 86% of lung cancer cases, including cases caused by passive exposure to smoke exhaled by other smokers. These chances increase if a person started smoking tobacco at a young age. Passive smoking poses a lesser threat, but is still dangerous—it is known that passive smokers (who are usually exposed to smoke at work or at home) have a 25% higher risk of lung cancer compared to people who are not exposed to the smoke of cigarettes. Regular heavy exposure to environmental tobacco smoke can increase the risk of lung cancer by 50% ( National Cancer Institute ).

Genetics and lung diseases in one’s genetics can also become significant risk factors of lung cancer. For example, if a person’s mother, father, sibling, aunt, uncle, or grandparent has had lung cancer, the chances of this person developing lung cancer slightly increases. At the same time, it has not been yet researched whether genes indeed increase cancer chances, or they increase individuals’ susceptibility to this disease. As for lung diseases, some of them are known to affect the chances of cancer development. In particular, among such diseases are tuberculosis and chronic obstructive pulmonary disease. Other illnesses like chronic bronchitis and emphysema can cause scarring in the lungs, which means the increase of the amount of tissue in them—and as it is known, cancer is an uncontrolled division of cells, and the respective multiplication of tissues ( Healthline ).

As for other environmental factors , one of the most significant among them is the exposure to asbestos fibers and similar materials. Usually, a person is exposed to these silicate materials at the workplace: technical works, such as thermal and acoustic insulation, involve the usage of asbestos. Nowadays, asbestos is limited or even prohibited from usage, since it has been proven that asbestos materials can cause both lung cancer and mesothelioma (cancer of the lungs’ pleura, as well as cancer of peritoneum—a lining of the abdominal cavity). Even non-smoking asbestos workers have a five times higher risk of developing lung cancer; as for the smoking asbestos workers, their chances to get cancer are up to ninety-fold greater than nonsmokers ( MedicineNet.com ).

As it can be seen, lung cancer does not develop on its own, but is triggered by a number of factors. The first and foremost of them is smoking tobacco, both active and passive. Exposure to asbestos materials also increases a person’s chances to get lung cancer. Also, genetics and past lung illnesses can lead to the development of this type of cancer. The cure for lung cancer is not finalized, and remains an epidemic.

“Lung Cancer Symptoms, Causes, Treatment.” MedicineNet. N.p., n.d. Web. 12 Aug. 2015.

“Lung Cancer Risks and Causes.” CancerResearch UK. N.p., n.d. Web. 12 Aug. 2015.

“Lung Cancer Causes.” Healthline. N.p., n.d. Web. 12 Aug. 2015.

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Cancer: A Very Short Introduction

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Cancer: A Very Short Introduction explains, in non-technical language, what cancer is and what it does. Why, despite constant improvements in treatment techniques, has cancer proved to be so hard to tackle? Why does cancer remain one of the largest causes of death worldwide? This VSI examines the different examples of cancer healthcare from around the world. It also investigates the political and economic context to cancer care and examines the trends in diagnosis and treatment of the disease. The future of cancer care and the alternative and complementary approaches to cancer care are also outlined.

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Essay on Cancer for Students and Children

500+ words essay on cancer.

Cancer might just be one of the most feared and dreaded diseases. Globally, cancer is responsible for the death of nearly 9.5 million people in 2018. It is the second leading cause of death as per the world health organization. As per studies, in India, we see 1300 deaths due to cancer every day. These statistics are truly astonishing and scary. In the recent few decades, the number of cancer has been increasingly on the rise. So let us take a look at the meaning, causes, and types of cancer in this essay on cancer.

Cancer comes in many forms and types. Cancer is the collective name given to the disease where certain cells of the person’s body start dividing continuously, refusing to stop. These extra cells form when none are needed and they spread into the surrounding tissues and can even form malignant tumors. Cells may break away from such tumors and go and form tumors in other places of the patient’s body.

Types of Cancers

As we know, cancer can actually affect any part or organ of the human body. We all have come across various types of cancer – lung, blood, pancreas, stomach, skin, and so many others. Biologically, however, cancer can be divided into five types specifically – carcinoma, sarcoma, melanoma, lymphoma, leukemia.

Among these, carcinomas are the most diagnosed type. These cancers originate in organs or glands such as lungs, stomach, pancreas, breast, etc. Leukemia is the cancer of the blood, and this does not form any tumors. Sarcomas start in the muscles, bones, tissues or other connective tissues of the body. Lymphomas are the cancer of the white blood cells, i.e. the lymphocytes. And finally, melanoma is when cancer arises in the pigment of the skin.

Get the huge list of more than 500 Essay Topics and Ideas

Causes of Cancer

In most cases, we can never attribute the cause of any cancer to one single factor. The main thing that causes cancer is a substance we know as carcinogens. But how these develop or enters a person’s body will depend on many factors. We can divide the main factors into the following types – biological factors, physical factors, and lifestyle-related factors.

Biological factors involve internal factors such as age, gender, genes, hereditary factors, blood type, skin type, etc. Physical factors refer to environmental exposure of any king to say X-rays, gamma rays, etc. Ad finally lifestyle-related factors refer to substances that introduced carcinogens into our body. These include tobacco, UV radiation, alcohol. smoke, etc. Next, in this essay on cancer lets learn about how we can treat cancer.

Treatment of Cancer

Early diagnosis and immediate medical care in cancer are of utmost importance. When diagnosed in the early stages, then the treatment becomes easier and has more chances of success. The three most common treatment plans are either surgery, radiation therapy or chemotherapy.

If there is a benign tumor, then surgery is performed to remove the mass from the body, hence removing cancer from the body. In radiation therapy, we use radiation (rays) to specially target and kill the cancer cells. Chemotherapy is similar, where we inject the patient with drugs that target and kill the cancer cells. All treatment plans, however, have various side-effects. And aftercare is one of the most important aspects of cancer treatment.

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• Open access
• Published: 07 May 2024

Immune checkpoint inhibitor (ICI)-based treatment beyond progression with prior immunotherapy in patients with driver-gene negative advanced non-small cell lung cancer

• Min Wang 1 ,
• Xuquan Jing 1 ,
• Feihu Chen 1 ,
• Shuangqing Lu 1 &
• Yulan Sun 2  

BMC Cancer volume  24 , Article number:  569 ( 2024 ) Cite this article

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No definite conclusion has yet to be reached for immunotherapy beyond progression(IBP) of first-line immunotherapy as the second-line treatment for advanced NSCLC patients with negative driver genes. Therefore a retrospective study was conducted to evaluate the efficacy of IBP in this population and investigated whether the cycles best response and progressive mode of first-line immunotherapy could affect the results.

Patients and methods

The clinical data of patients with advanced NSCLC whose response was evaluated as progressive disease (PD) after receiving a PD-1/PD-L1 inhibitors as first-line therapy were retrospectively collected and the patients were assigned to the IBP and non-IBP groups. The overall survival (OS), progression-free survival (PFS) were evaluated between the two groups. The survival effects of cycles best response and progressive mode of first-line immunotherapy were also evaluated.

Between January 2019 and January 2022, a total of 121 patients was evaluated as PD after first-line immunotherapy in our institution; 53 (43.8%) patients were included in the IBP group and 68 (56.2%) patients were included in the non-IBP group. The OS and PFS were no significantly different between the two groups in whole population. Further analysis revealed the OS was prolonged with the prolongation of first-line medication cycle. The median OS was 15.4m (15.4 vs 10.8 p =0.047) 16.1m (16.1 vs 10.8 p =0.039), 16.3m (16.3 vs 10.9 p =0.029) for patients with ≥4, ≥6, ≥8 cycles in first-line immunotherapy, respectively. The advantages of OS and PFS were also seen in the subgroup of PR (best response) and oligo progression of first-line immunotherapy.

Conclusions

The clinical outcomes of IBP were similar to those of non-IBP in patients with PD after first-line immnuotherapy in advanced NSCLC. But more cycles, PR as best response and oligo progression in first-line was benefit.

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Introduction

According to the Global Cancer Statistics 2020, lung cancer is remained the leading cause of cancer death [ 1 ]. Among them, patients with non–small-cell lung cancer (NSCLC) pathological type accounts for 85%, while the 5-year survival rate was less than 16% [ 2 ]. Therefore, there is an urgent need for improving the survival of patients with advanced non-small cell lung cancer (aNSCLC).

Starting from the clinical development of second-line monotherapy, Immune checkpoint inhibitors (ICIs), including anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) antibodies, have contributed greatly to improving the survival rate to driver gene-negative aNSCLC patients, no matter in first-line or second-line therapy [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. However, there is no definite conclusion has yet to be reached for whether ICIs benefit patients beyond progression (IBP) of first-line immunotherapy as the second-line treatment for aNSCLC patients. According to post-hoc analyses of Keynote 010 study, 14 patients were retreated with Pembrolizumab after PD and achieved an ORR of 42.9% and a DCR of 78.6% [ 9 ]. And 51% of atezolizumab-arm patients who developed PD in OAK study continued to receive atezolizumab as treatment beyond progression (TBP). OS in TBP group was longer than switched to non-protocol anti-cancer therapy and no follow-up anti-tumor treatment (12.7 months vs. 8.8 vs, 2.2 months) [ 10 ]. These studies suggested that re-receiving PD-1 inhibitors still a possible benefit when tumors progress.

In this context, we conducted this retrospectively study under to investigate the effective of IBP and non-IBP treatment in aNSCLC patients. Furthermore, we evaluated whether the cycles, best response and progressive mode of first-line immunotherapy could affect the results.

Materials and methods

We retrospectively screened the records of advanced NSCLC patients whose response was evaluated as progressive disease (PD) after receiving a PD-1/PD-L1 inhibitors as first-line therapy in Shandong Cancer Hospital and Institute (Jinan, Shandong, China) between January 2019 and January 2022. The inclusion criteria were: (1) Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1; (2) NSCLC confirmed by pathological or cytologically diagnosis; (3) stage IV or recurrent disease according to the eighth edition of the TNM classification for lung cancer; (4) received at least two cycles of ICIs in first-line treatment; (5) confirmed PD after first-line therapy using radiological examinations including chest computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), bone scan, ultrasound examination, or CT of the abdomen. The exclusion criteria were: (1) EGFR mutations or ALK/ROS1 rearrangements detected by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) or next generation sequencing (NGS); (2) Patients with multiple primary tumors; (3) without progression or loss of follow-up in first-line therapy. Anonymized clinical data were collected from medical records, including gender, age, smoking status, histological subtype, gene alteration status, PD-L1 expression status, ECOG PS score, liver/brain metastases, best response to the first-line, progression mode of first-line, first/second-line therapy regimen.

Patients who were treated with ICIs for more than 2 cycles after PD were defined as IBP, while those who received ICI treatment for less than 2 cycles or discontinued it due to the PD were defined as non-IBP.

Assessment of response

The response evaluation of tumors was based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. evaluation was performed routinely every 6–8 weeks after starting treatment with the PD-1/PD-L1 inhibitor. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. AEs that occurred during hospitalization were registered and graded by their attending doctor timely, while AEs that occurred outside the hospital were mainly based on patients’ initiative report. In our study, oligo progression was defined as ≤ 2 sites and ≤ 2 lesions of progression. Extensive progression was defined as≥ 3 sites and ≥ 3 lesions of progression.

The primary study objective was overall survival (OS), defined as the time from the initiation of the post-PD treatment to death from any cause. The secondary objectives were progression-free survival (PFS). PFS was defined as the time from the initiation of the post-PD treatment to disease progression or death from any cause, whichever came first. The date of the last follow-up was October 1,2022 and the follow-up rate was 92.6%.

Statistical analysis

All statistical analyses were performed using GraphPad Prism software version 8.0 (GraphPad Software, Inc., United States) and SPSS statistical software version 20.0 (IBM Corp., United States). The comparisons of patients’ baseline characteristics, tumor response in the two groups were analyzed using the Chi-square test and Fisher’s exact test. Univariate survival analysis was performed using the Kaplan–Meier method. Multivariate survival analysis was performed by a Cox proportional hazards model to evaluate the independent prognostic factors associated with improved survival. The Kaplan–Meier method was used to calculate OS and PFS. The difference in survival curves between the two groups was estimated by the log-rank test. Two-sided P values < 0.05 were considered statistically significant.

Patients characteristics

Between January 2019 and January 2022, 319 patients received immunotherapy in our institution. 94 patients were excluded for without progression, and 69 patients were excluded for lost to follow up in first-line. 10 patients were excluded for with other primary tumors, and 5 patients were excluded for with EGFR mutations in post-test. 141 aNSCLC patients was finally included due to treated with ICIs in second-line after immunotherapy PD in first-line. Then 20 patients were excluded for with <2 cycles IO+ChT treatment in first-line. As a result, a total of 121 patients who received PD-1/PD-L1 inhibitor as the second-line or later therapy were enrolled in the study (Fig. 1 ). According to the therapeutic modality, there were 53 patients in the IBP group and 68 patients in the non-IBP group. The last follow-up time was October 1, 2022. 48 patients had died by the end of the follow-up, and 73 patients were still alive. The median follow-up time was 5.6 months (range, 0.2– 29.0 months) for surviving patients and 13.1 months (range, 0.2–29.0 months) for all patients. The baseline characteristics of all patients in both groups are shown in Table 1 . There were no differences between the two groups in the distribution of most variables except for treatment features. The median age of the patients in the two groups was 62 years, and the age range was 27 to 76 years. Fifty- three (43.8%) patients received IBP treatment, and 68 (56.2%) patients received non-IBP treatment. Eigthy-seven (71.9%) patients have adenocarcinoma pathology, 34 (28.1%) patients have squamous pathology. Thirty-three (28.1%) patients had brain metastases, and 20 (16.5%) patients had liver metastases. Sixty-four (52.9%) patients had never smoked. Fifty-four patients underwent PD- L1 detection: 17 (14.0%) patients had a level <1%, 19 (15.7%) patients had a level from 1 to 49%, and 18 (14.9%) patients had a level ≥ 50% (Table 1 ). The loss of follow-up rate was 7.4%.

Study diagram

The median PFS1 in the IBP group and non-IBP group in first-line therapy was 7.6 and 9.4 months, respectively. PFS1 was not significantly different between the two groups ( p =0.103 Fig. 2 ). The median OS in the IBP group and non-IBP group was 14.1 and 10.8 months, and not statistically difference ( p =0.063 Fig. 3 A). The OS rates at 1 year in the IBP group and non-IBP group were 37.7% and 13.2%, respectively. The median PFS was 8.7 months for the patients receiving IBP treatment and 4.1 months for those receiving non-IBP treatment in second-line therapy. The PFS was longer in the IBP group than in the non-IBP group ( p < 0.001, Fig. 3 B). Partial subgroup analysis of OS was in Fig. 3 C.

IBP versus non-IBP in second-line treatment of PFS1 in advanced NSCLC patients. Abbreviations: PFS, progression-free survival

IBP versus non-IBP in second-line treatment of OS ( A ) and PFS ( B ) in advanced NSCLC patients. Subgroup analysis of OS ( C ). Abbreviations: IBP, immunotherapy beyond progression; NSCLC, non-small-cell lung cancer; OS, overall survival

In the subgroup of 109 patients with ≥4 cycles in first-line immunotherapy, the OS and PFS were statistically different between the IBP group and non-IBP group (median OS: 15.4 vs. 10.8 months, respectively, p =0.047 Fig. 4 A; median PFS: 8.7 vs. 4.4 months, respectively, p <0.001, Fig. 4 B). And in the subgroup of the 90 patients with ≥6 cycles in first-line immunotherapy, the OS and PFS were statistically different between the IBP group and non-IBP group (median OS: 16.1 vs. 10.8 months, respectively, p =0.039, Fig. 4 C; median PFS: 8.7 vs. 4.7 months, respectively, p =0.01, Fig. 4 D). Then in the subgroup of the 67 patients with ≥8 cycles in first-line immunotherapy, the OS and PFS were statistically different between the IBP group and non-IBP group (median OS: 16.3 vs. 10.9 months, respectively, p =0.029, Fig. 4 E; median PFS: 11.9 vs. 5.7 months, respectively, p =0.006, Fig. 4 F).

OS ( A ) and PFS ( B ) in patients with ≥4 cycles in first-line immunotherapy subgroup of aNSCLC between IBP and non-IBP. OS ( C ) and PFS ( D ) in patients with ≥6 cycles in first-line immunotherapy subgroup of aNSCLC between IBP and non-IBP. OS ( C ) and PFS ( D ) in patients with ≥8 cycles in first-line immunotherapy subgroup of aNSCLC between IBP and non-IBP

In the subgroup of the 48 patients with PR as best response in first-line immunotherapy, the OS was different between the IBP group and non-IBP group (median OS: 18.9 vs. 10.2 months, respectively, p =0.041, Fig. 5 A). The PFS in the IBP group was longer than that in the non-IBP group (median PFS: 11.6 vs. 4.4 months, respectively, p =0.023, Fig. 5 B). The OS of the 63 patients with SD as best response in first-line immunotherapy was similar between the IBP group and non-IBP group (median OS: 14.1 vs. 13.5 months, p =0.389, Fig. 5 C). The PFS in the IBP group was longer than that in the non-IBP group (median PFS: 7.9 vs. 4.2 months, p =0.004, Fig. 5 D).

OS ( A ) and PFS ( B ) in patients with PR as best response in first-line immunotherapy subgroup of aNSCLC between IBP and non-IBP. OS ( C ) and PFS ( D ) in patients with SD as best response in first-line immunotherapy subgroup of aNSCLC between IBP and non-IBP

The IBP group showed a longer OS (median OS: 16.3 vs. 10.8 months, respectively, p =0.035, Fig. 6 A) and PFS (median PFS: 9.4 vs. 4.0 months, respectively, p =0.002, Fig. 6 B) than the non-IBP group for oligo progression subgroups. However, the OS (median OS: 13.1 vs. 13.5 months, respectively, p = 0.626, Fig. 6 C) were not different between the two groups in the extensive progression subgroups. The PFS was longer in the IBP group than in the non-IBP group (median PFS: 6.7 vs. 4.4 months, respectively, p = 0.014, Fig. 6 D).

OS ( A ) and PFS ( B ) in patients with oligo progression in first-line immunotherapy subgroup of aNSCLC between IBP and non-IBP. OS ( C ) and PFS ( D ) in patients with extensive progrssion in first-line immunotherapy subgroup of aNSCLC between IBP and non-IBP

Prognostic factors

The clinical characteristics of the patients were evaluated to determine their prognostic value for OS (Table 2 ). Univariate analysis indicated that age and cycles of first-line immunotherapy were associated with survival. Patients ≤65 ( p =0.045) and first-line immunotherapy ≥8 cycles ( p =0.046) had a better OS. For PFS, univariate analysis revealed that histology, liver meta and cycles of first-line immunotherapy were significant favorable prognostic factors (Table 3 ). Multivariate analysis revealed that the liver meta ( p = 0.007) was favorable prognostic factors for PFS.

The rate of adverse events(AEs) in two groups was listed in Table 4 . The incidence of any grade AEs in IBP group and non-IBP group was 32.1% and 29.4%, respectively. The rate of grade≥3 adverse events was 7.5% in the IBP group, compared to 5.9% in the non-IBP group. No patient died from AEs.

The available retrospective studies showed inconsistent clinical results. According to Enomoto et al, no significant benefits were associated with continuation of nivolumab for advanced NSCLC patients [ 11 ]. And two small sample studies reported no benefit from similar ICI rechallenge [ 12 , 13 ]. However, several studies showed benefit in IBP group. A real-world study of more than 4,000 aNSCLC patients from the USA showed IBP patients had a longer OS (11.5 vs. 5.1 months p < 0.001) in comparison to non-IBP patients [ 14 ]. A multicenter study from Italy reported patients treated with nivolumab monotherapy as a second or subsequent line received longer OS (17.8 vs. 3.7 months p <0.0001) than not treated with nivolumab monotherapy beyond progression (NTBP) 15 . And a study of 125 aNSCLC patients by Ge et al. reported longer OS (26.6 vs. 9.5 months p < 0.001) in the IBP group [ 16 ]. Another research by Tian et al. also reported longer OS (15.7 vs. 5.0 months p < 0.001) in the IBP group [ 17 ]. Overall, the role of immunotherapy with ICI TBP in patients with NSCLC remains incompletely elucidated. In our study, there was no statistical difference of OS between two groups but results showed longer OS of IBP group than non-IBP group (14.1m vs 10.8m p =0.063). And IBP significantly prolonged PFS (8.7m vs 4.1m p <0.001). Previous studies included patients with driver genes and IBP >2 lines of therapy in their inclusion may explain the gap with our study in OS. In addition, previous studies used immune monotherapy as an option for immune continuation therapy, yet our immune monotherapy accounts for only 1.7%. The duration of first-line immunotherapy has always been a controversial issue due to the special mechanism of immunotherapy. In our study univariate analysis of OS and PFS suggested that first-line immunotherapy over 8 cycles was a favorable factor. According to the subgroup of first-line immunotherapy cycles analysis the OS and PFS were statistically different between the IBP group and non-IBP group in patients with ≥4 cycles and ≥6 cycles in first-line immunotherapy. Consistent with univariate analysis, patients with ≥8 cycles in first-line immunotherapy received longer OS (16.3m) and PFS (10.9m) than ≥4 cycles and ≥6 cycles. Our forest maps also show this trend of longer first-line cycles availability and longer survival. Lu Shun et al. presented their results about an exploratory research of response characteristics of the RATIONALE 304 study at the 2022 Chinese Society of Clinical Oncology (CSCO) meeting. Of 128 non-squamous NSCLC patients, 65 (50.8%) achieved first remission after 2 cycles 40 (31.3%) after 4 cycles and 100% after > 4 cycles [ 18 ]. Among 76 responder patients in a retrospective study of 262 patients (all cancer types) treated with an anti-PD-L1 monotherapy in a phase 1 trial, the median time from therapy initiation to response was 2 months [ 19 ]. But 28 responder patients responsed until 3 months later. Our study included patients treated with ≥2 cycles (about 2 months) in first-line and results, while patients with ≥4 cycles (about 3 months) received longer survival. And our results suggested that the longer first-line cycles the longer survival. Studies reported that the incidence of pseudoprogression in non-small cell lung cancer was about 5.4% [ 20 ]. And approximately 2.2% of patients assessed as progressing under traditional RECIST 1.1 criteria had a CR or PR as measured by iRECIST(immune-related RECIST) [ 21 ]. Different from RECIST 1.1, iRECIST defines the PD determined by RECIST 1.1 as immune unconfirmed progressive disease (iUPD), and re-evaluates after 4-8 weeks. Then the next evaluation confirms progress as immnue confirmed progressive disease (iCPD) or confirms as iCR, iPR, iSD for next assessment [ 35 ]. Patients with ≥4 cycles of therapy may have overcome atypical responses such as pseudoprogression and are more likely to benefit from immunotherapy. The statistical difference of ≥4 cycles suggested that the first-line immunization with 4 cycles before imaging efficacy assessment may be more consistent with the actual disease status of patients with antiimmunotherapy.

The effect of best response of initial immunotherapy on survival has been explored in studies. Ge et al's findings showed that IBP patients had longer OS and PFS than non-IBP patients, whether in the subset of patients who responded to the initial immunotherapy or in those who did not [ 16 ]. In a similar vein, Ricciuti et al. observed a survival benefit for patients in the IBP group compared to non-IBP patients, independent of the best response to the initial immunotherapy, whether disease control or PD [ 15 ]. This was based on a subgroup analysis of IBP with nivolumab. Both studies included patients with multiple lines of IBP as well as a subgroup of patients with EGFR mutation. However, in previous studies, immunotherapy had a shorter OS in EGFR-positive patients and had an increased risk of interstitial pneumonia [ 2 , 22 , 23 ]. Interestingly patients who had a positive response to earlier immunotherapy had greater survival benefit than those who had a negative response as best response. The mPFS of patients in (CR/PR) group verus (SD/PD) group was 7.3m verus 4.3m ( P <0.0001), and mOS of these patients was 22.8m verus 15.7m ( P <0.0001). The ORR for patients who experienced the best response to the first round of ICI treatment—CR/PR/SD/PD was 100%, 6.7%, 10.1%, and 10.2%, respectively [ 17 ]. The same phenomenon was observed in melanoma [ 24 , 25 ]. Our results showd IBP benefit in both OS (18.9 vs. 10.2 months, p =0.041) and PFS (11.6 vs. 4.4 months, p =0.023) in the PR as best response in first-line immunotherapy subgroup. Patients who responded well to prior immunotherapy received increased survival benefit from the second-line ICI-based treatment. Although the exact mechanism behind this finding is unclear, one possible explanation could be that patients who responded well to previous immunotherapy produced immune memory cells [ 26 , 27 ], thereby rapidly rebuilding the immune system during the next round of immunotherapy.

The clinical concept of OPD (oligo progression disease) was first introduced in 2011 in order to differentiate the degree of progression to identify patients with potentially manageable progression [ 28 ]. OPD occurs after an initial response to systemic therapy and anatomically limited tumor progression in otherwise controllable. In previous studies, OPD mostly described aNSCLC with driver genes. The OPD rate of patients with targeted therapy was 33%-72% [ 29 , 30 , 31 ]. However, in the studies of immunotherapy, OPD rate of patients is reported to be lower as 10%-55.3% [ 32 , 33 ]. Consistent with previous studies, the OPD rate in our study for first-line immunotherapy was 47.1% (57/121), slightly less than extensive progression. In addition, patients in the OPD subgroup achieved longer OS (16.3 vs 10.8 monthes p =0.035) and PFS (9.4 vs 4.0 monthes p =0.002) with continued immunotherapy after progression. The best management for OPD patients remains unclear cause lack of published prospective data available. Previous studies suggest that the addition of local therapy and maintenance of the original systemic therapy regimen is feasible to regain control of disseminated tumors [ 32 , 33 ]. They reported the benefit of adding local radiation therapy in combination with immunotherapy. Since only 23% (6/26) of patients in our IBP group added topical treatment, no further analysis was performed. Local radiation therapy can enhance the immunostimulatory effect and allow systemic therapy to continue by overcoming the few subclones that develop resistance [ 34 ] and is increasingly seen as a promising combination treatment strategy with ICIS. However, the optimal dose of radiation therapy to induce immune stimulation and the appropriate sequence of treatment (sequential or concurrent) were needed further prospective studies are needed to further elucidate.

Like all retrospective analyses, our study has limitations. First, the small sample size affected the statistical power and may have led to selection and measurement bias. Despite adjustment by the Cox regression model, confounding factors may still have been present. Further analysis with a larger sample size is necessary in the future. Due to the moderate sample size, we did not differentiate and assess the efficacy of each treatment regimen in the combination group, and this issue requires more research. More potential influencing factors, such as smoking [ 36 ] and immunotherapy concomitant drugs [ 37 ], also need more detailed data for further study. And These results will need to be confirmed by prospective randomized studies in sizable populations.

In conclusion, the clinical outcomes of IBP were similar to those of non-IBP in patients with PD after first-line immnuotherapy in advanced NSCLC. But IBP is an effective therapy options for patients who with ≥4 cycles immunotherapy PR as best response or oligoprogression in first-line. Our observations may provide direction for treatment options for patients after progression of first-line immunotherapy. Larger trials are needed for further confirmation.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Non-small cell lung cancer;

Immune checkpoint inhibitor

Immunotherapy beyond progression

Anti-programmed cell death-1

Anti-programmed cell death ligand-1

Progressive disease

Chest computed tomography

Positron emission tomography

Magnetic resonance imaging

Response Evaluation Criteria in Solid Tumors

Adverse events

Common Terminology Criteria for Adverse Events

Overall survival

Progression-free survival

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This work was supported by CSCO-Pilot Cancer Research Fund [grant number: Y-2019AZZD-0352].

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Min Wang, Xuquan Jing, Feihu Chen & Shuangqing Lu

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Min Wang and Xuquan Jing contributed equally to this work. YLS: Conception and design，MW and XQJ: analysis and interpretation of data, drafting the manuscript, FHC and SQL: data acquisition.  All authors read and approved the final manuscript.

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Wang, M., Jing, X., Chen, F. et al. Immune checkpoint inhibitor (ICI)-based treatment beyond progression with prior immunotherapy in patients with driver-gene negative advanced non-small cell lung cancer. BMC Cancer 24 , 569 (2024). https://doi.org/10.1186/s12885-024-12315-5

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The top 100 cited articles in lung cancer – a bibliometric analysis

Aim of the study.

To analyze the 100 most cited lung cancer articles published in biomedical literature in the last 44 years. We pointed out developments in lung cancer and aimed to create convenient access for the researchers of this dynamic field.

Material and methods

We accessed the WoS database (accessed: 15.07.2019) using the keyword “lung cancer” between 1975 and 2019. The top 100 cited articles were analyzed by topic, journal, author, year, institution, level of evidence, adjusted citation index and also the correlations between citation, adjusted citation index, impact factor and length of time since publication.

A total of 240,701 eligible articles were identified and we chose the top 100 articles cited in the field of lung cancer. The mean number of citations for these articles was 1879.82 ±1264.78. The most cited article was (times cited: 7751) a study by Lynch et al. The New England Journal of Medicine (NEJM) made the greatest contribution to the top 100 list with 32 articles, and the most cited article also originated from NEJM. The highest number of citations was seen in 2017 with 18,393 citations while the highest number of publications was seen in 2005 with 12 publications.

Conclusions

Oncology is a developing field and we have seen the evolution in this area through the treatment of lung cancer in recent years. The first 100 articles in our analysis not only reflect the landmark articles with the greatest impact on lung cancer research, but also acknowledge the most productive authors and institutions that have contributed to the list with their articles.

Introduction

Lung cancer is an important health problem with an increasing incidence. In most European countries, lung cancer has increased so dramatically that it may be considered one of the major health problems in the last century [ 1 ]. The most common causes of cancer-related death are cancers of the lung and bronchus (24%), prostate (10%) and colorectum (9%) in men, and lung and bronchus (23%), breast (15%), and colorectum (8%) in women [ 2 ]. Although lung cancer has long been characterized by late-stage diagnosis and poor survival, encouraging results have been achieved for lung cancer screening in high-risk populations in the last decade and there has been significant progress in systemic treatments for molecular subgroups of patients with advanced disease. Furthermore, within the last ten years, new molecular targets have emerged, next-generation drugs with more specific target effects have been introduced, and targeting specific resistant mutations is expected to advance the treatment of lung cancer by creating a chronic therapeutic pathway [ 3 ]. This bibliometric study demonstrates the development of lung cancer treatment over the years.

Bibliometric studies represent an important study type showing the trend topics in a given field. Numerous medical and surgical specialists have published the most cited articles in their specialties in the form of bibliometric analysis such as general surgery [ 4 ], anesthesiology [ 5 ], orthopedics [ 6 ], otolaryngology [ 7 ], radiology [ 8 ] and plastic surgery [ 9 ]. The first bibliometric analysis was penned by Garfield and published in JAMA in 1987 [ 10 ]. He also continued with new bibliometric studies in different fields of medical science.

The purpose of our study was to identify and analyze the 100 most cited lung cancer articles published in biomedical literature in the last 44 years. We determined the number of citations with ranking, average citations per year (ACY), citations and publications by year, publishing journal, institution and country of origin, the most common subject of frequently cited articles, authorship status of classical papers and correlation analyses between citation, ACY, Impact Factor (IF) and length of time since publication in years.

Study design

Study type: retrospective clinical study, Level of evidence: 3 or Group B (Scottish Intercollegiate Guidelines Network; SIGN) [ 11 ].

Data collection and inclusion criteria: In this paper reporting a bibliometric citation analysis, data were obtained from Thomson Reuters’ WoS Core Collection database (Philadelphia, Pennsylvania, USA) and PubMed (US National Library of Medicine-National Institutes of Health). We accessed the WoS database (accessed: 15.07.2019) using the keyword “lung cancer” between 1975 and 2019. We identified 240,701 articles and conducted an analysis of the top 100 cited articles among these hits shown in Table 1 [ 12 – 111 ]. Articles not relevant to lung cancer were excluded from our study and we included original research articles, editorials, correspondences, review articles and case reports. We also utilized the PubMed database to obtain additional data related to the study. Two of the authors (NSS and EC) independently identified T100 with consensus. The difference in time since publication among the top 100 articles may cause a bias as older articles may be more likely to have obtained more citations owing to a longer citable period. The Web of Science, Citation Report feature displays bar charts for the number of items published each year and calculates the average number of citations per year per publication. Due to this bias, we used the ACY for each article.

The top 100 cited articles in lung cancer

ACY – average citations per year

Statistical analysis

A commercial software (SPSS version 16.0, SPSS, Chicago IL, USA) was used for the statistical analysis. The Kolmogorov-Smirnov test was used to analyze the normal distribution of data. Spearman’s correlation was used to evaluate the associations between citation, ACY, IF and length of time since publication. A p- value < 0.05 was accepted as statistically significant.

Ethical statement

All authors declare that the study was conducted according to the principles of the World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. This study did not require approval from an ethics committee as it was designed as a bibliometric analysis or citation analysis of existing published classical studies.

We identified 240,701 articles from 1975 to 2019. The language was English for all articles. The 100 most cited articles in lung cancer are listed in Table 1 , arranged in descending order according to the number of times cited. The number of citations ranged from 7751 to 889, and the mean number of citations per article was 1879.82 ±1264.78 (range: 7751–889). We found that the most cited article (times cited: 7751) on lung cancer was a study by Lynch et al. with the following title: “Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmallcell lung cancer to gefitinib” published in N Engl J Med 2004; 350: 2129-1239. The least cited article (times cited: 889) on lung cancer was penned by Imielinski et al. with the following title: “Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing” and published in Cell 2012; 150: 1107-1120. Additionally, we determined that there were 84 articles that got more than 1000 citations and the article with the highest ACY was the article that ranked 16 in the T100 list. The article with the highest ACY was a randomized phase 3 trial by Borghaei et al. , titled “Nivolumab versus docetaxel in advanced nonsquamous non-smallcell lung cancer” and published in N Engl J Med 2015; 373: 1627-1639. The highest number of citations was seen in 2017 with 18,393 citations while the highest number of publications was seen in 2005 with 12 publications.

The oldest article was a review published in Nature 1985; 316: 823-826 titled “Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer” by Cuttitta et al. with 1280 citations and ACY 36.57 ACY. The newest study in the T100 list was a phase 3 trial conducted by Rittmeyer et al. published in Lancet 2017; 389: 255-265 with the following title: “Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial”, with 926 citations and ACY 308.67.

In the T100 list, 82 were clinical studies and 18 were experimental studies. The 82 clinical articles included 42 randomized controlled studies, 8 review articles, 4 meta-analyses, 2 case reports and other clinical studies. Fifty-nine of these 82 clinical articles were treatment-based studies. The treatment-based studies are classified in Table 2 according to the level of evidence.

Type of treatment and level of evidence of the treatment based clinical articles ( n = 59)

EGFR – epidermal growth factor receptor, ALK – anaplastic lymphoma kinase

While 32 of these articles were published in NEJM, 16 were published in the Journal of Clinical Oncology , 7 in The Lancet , 7 in Science , etc. ( Table 3 ).

List of journals with published articles

All of the T100 articles were published across 23 different journals. Eighty-five of the T100 articles were published in 14 journals that had IF ≥ 10.336. We determined that the mean IF of these 23 journals was 23.42 ±19.90 (range: 79.26–2.12) (according to Clarivate Analytics, 2017). The “Quartile Score” category was Q1 for all the journals (according to SCImago Journal and Country Rank, 2019). Most of the articles were published in NEJM, and NEJM was also the journal with the highest IF. The correlation analysis for the number of citations, ACY, IF and length of time since publication parameters in the T100 list revealed a positive correlation between citation and ACY ( r = 0.744, p = 0.00) and between ACY and IF ( r = 0.236, p = 0.018), whereas a negative correlation was observed between ACY and length of time since publication ( r = –0.562, p = 0.00) and between IF and length of time since publication ( r = –0.266, p = 0.008). There was no correlation between citation and length of time since publication or between citation and IF ( Fig. 1 ).

Correlation analysis for the citation numbers, ACY, IF, length of time since publication parameters

According to the geographic origin of the T100 list, the USA ( n = 74) was the most contributing country, followed by Japan and Canada ( Table 4 ). We determined that the most commonly listed institution was the University of Harvard (USA), which was listed 27 times in the top 100 cited articles ( Table 5 ). Moreover, 11/19 of the institutions that published eight or more publications were found to be in USA.

Geographic origin of the top 100 articles

Institutions of origin with 8 or more of the top 100 cited articles

It was seen that 3 authors were the first author in more than one article in the T100 list’s top 12 authors ( Table 6 ). Herbst RS contributed to 8 articles and was the first author in 4 of them. Janne PA, Johnson BE and Johnson DH also contributed to 8 articles. However, Herbst RS had the highest number of articles as first author. The “Web of Science” category analysis of the T100 in the field of the lung cancer revealed that these articles ranked under general internal medicine ( n = 47), oncology ( n = 33), multidisciplinary sciences ( n = 13), cell biology ( n = 8) and respiratory system ( n = 6) as the most featured branches.

The most common authors with 6 or more in the top 100 cited articles

Lung cancer is the major cause of cancer-related deaths worldwide. There are two main types of this cancer: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 80% of all lung cancers. Despite the advances in surgical methods and advances in radiotherapy and chemotherapy, non-small-cell lung cancer continues to account for the majority of lung cancers and is associated with a 5-year survival rate of 15% [ 112 ].

There have been significant advances in the treatment of lung cancer in the last 40 years, and this is reflected in the scientific literature. A better understanding of disease progression coupled with targeted immunological therapies has led to increased survival rates.

We found that in our top 100, 28% of the articles were less than 10 years old while 72% of them were older than 10 years. Articles with a higher number of citations are indeed expected to be older. Year of publication and number of citations for an article are closely linked, and the number of citations grows over time. Needless to say, citation is an important metric, which shows the quality and attractiveness of an article; however, a certain amount of time should be allowed to pass after the publication of an article for it to reach a higher number of citations. For that reason, number of citations alone is inadequate to determine the quality of an article. In this study, ACY was used to eliminate the time bias when evaluating older articles against newer articles. Of the T100, 18% were comparative studies, and there were 2 case reports in the T100 list. The two case reports were published in 2005. One of them was published in NEJM (times cited: 2549), and the other in Plos Med (times cited: 2073). Both were about EGFR mutations. It is noteworthy that a case report receives such a high number of citations. This may be due to the fact that EGFR mutations were popular in the 2000s. In the T100, 29% of the articles were noted to concern erlotinib (anti-EGFR), gefitinib (anti-EGFR) and EGFR mutations. The 1 st study with the highest number of citations was a study related to EGFR mutations, showing that EGFR mutations play an important role in the development stages of lung cancer treatments.

Immunotherapy has become one of the most promising treatments for several human cancers. In fact, James P. Allison and Tasuku Honjo were awarded with the Nobel Prize in medicine for their research on immune checkpoint blockade [ 113 , 114 ]. As a result, the immune check-point inhibitor (ICPI) may be regarded as an immunotherapy modality that started a new era in cancer treatment and remains a new trend topic. Especially in advanced non-small cell lung cancer (NSCLC), significant improvement has been observed in survival results with anti-PD-1 and PDL-1 drugs compared to chemotherapy. That shows the changing trends in cancer immunotherapy during the last decade. We can also see studies on immunotherapy in the T100 list. The most cited immunotherapy-related study in T100 was published in 2015 and received 2966 citations (ACY 593.2). It was published in N Engl J Med 2015; 373: 123-135 by Brahmer et al. with the following title: “Nivolumab versus docetaxel in advanced squamouscell non-smallcell lung cancer”. This study currently remains a new study of only 4 years old, and despite being a very young article, the number of citations it has received shows that the study in question involves a very important innovation. Moreover, this article has the highest ACY score in the T100 list. This shows that scientists are currently focused on immunotherapy. There are only 7 studies about immunotherapy in the T100, and the newest article in the T100 was published in Lancet 2017; 389: 255-265 by Rittmeyer, titled “Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial”. It is only a 2-year-old article; however, it has 926 citations with an ACY score of 308.67. When we list the articles based on ACY scores in descending order, the first 4 articles are immunotherapy-related and recent articles.

The correlation analysis showed a positive correlation between citation and ACY and between ACY and IF, whereas a negative correlation was found between ACY and length of time since publication and between IF and length of time since publication. This indicates that articles with high ACY scores have been published in journals with a high IF. Furthermore, younger articles have higher ACY scores and have been published in journals with a higher IF.

When we looked at the T100 list, another point of interest also caught our attention: there were very few articles related to small-cell lung cancer (SCLC). Only 3 articles were on small-cell lung cancer [ 115 – 117 ]. This either means that there has not been any significant advance in SCLC or scientists are less interested in this topic.

To the best of our knowledge, this is the first report of a citation analysis of lung cancer in the English literature. The first 100 articles in our analysis not only identify landmark articles that have the greatest impact on lung cancer research, but also acknowledge the most productive authors and institutions that contributed to the list with their articles. Oncology is a developing field in science, and we have seen its evolution through the treatment of lung cancer over the years. Briefly, bibliometric analyses for different medical disciplines and sub-specialties demonstrate the improvements in a given field from a nominative perspective. The present bibliometric citation analysis on lung cancer has covered several scientific fields, and we believe it enables the systematic identification of true landmark publications as well as the distribution of citations of these publications by year, main topic, institution, scientific journal, level of evidence, and correlation analysis, thereby providing a substantial contribution for oncological research.

The authors declare no conflict of interest.